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Lentiviral Nef increases T cell signaling activity, but the molecular nature of the stimulus involved is incompletely described. We explored CD4 T cell lipid raft composition in the presence and absence of Nef. Here, the E2 ubiquitin-conjugating enzyme UbcH7, which acts in conjunction with c-Cbl, is absent from lipid rafts. This Nef-mediated exclusion is associated with failure of ubiquitination of activated Vav. In the presence of Nef, lipid raft Cdc42 is activated and forms a ternary complex between the c-Cbl-interacting protein p85Cool-1/betaPix and c-Cbl, displacing UbcH7 from rafts. Suppression of p85Cool-1/betaPix expression restores UbcH7 raft localization and Vav ubiquitination and diminishes Cdc42 activity. Moreover, p85Cool-1/betaPix knockdown attenuates HIV replication. Thresholds for activation of signaling involve the intricate balance of positive and negative regulators. Here we provide evidence for Nef disruption of a negative regulator of T cell signaling in promoting HIV replication.

Original publication




Journal article



Publication Date





621 - 634


Blotting, Western, CD4-Positive T-Lymphocytes, Cell Cycle Proteins, Cell Line, Enzyme-Linked Immunosorbent Assay, Gene Products, nef, Guanine Nucleotide Exchange Factors, HIV, Humans, Immunoprecipitation, Membrane Microdomains, Microscopy, Confocal, Proto-Oncogene Proteins c-cbl, RNA, Small Interfering, Rho Guanine Nucleotide Exchange Factors, Signal Transduction, Ubiquitin-Conjugating Enzymes, Virus Replication, cdc42 GTP-Binding Protein, nef Gene Products, Human Immunodeficiency Virus